Asymmetric synthesis of functionalized pyrrolizidines by an organocatalytic and pot-economy strategy

Abstract

An efficient method has been developed for the enantioselective synthesis of tetrahydro-1H-pyrrolizin-3(2H)-ones starting from α,β-unsaturated aldehydes via a sequence of asymmetric Michael–oxidative esterification–Michal–reduction–reductive amination–lactamization reactions with high enantioselectivities (93–97% ee). The six-step reaction sequence can be conducted with the pot-economy synthetic strategy with only a one-step purification. The structure and absolute stereochemistry of the intermediates and products were confirmed by X-ray analyses of appropriate products.

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Indolizidine and the related azabicyclic ring systems constitute an important skeleton in many natural alkaloids with a wide spectrum of biological and pharmacological activities (Fig. 1). Owing to their biological activity and their scarcity in nature, many efforts have been devoted to the synthesis of these azabicyclic ring systems (Scheme 1). Among them, most syntheses have started from the natural chiral precursors, such as proline derivatives, or with the stoichimetric amount of chiral resources, and have been characterized by many steps of transformation. For example, total synthesis of the alkaloid (−)-absouline was accomplished in 8 steps by a key step reaction of a diastereoselective aminoconjugate addition to an enantiopure enoate,¹ while the syntheses of (−)-isoretronecanol and/or (−)-trachelanthamidine were revealed from a L-proline derivative after many reaction steps (Scheme 1a).² (−)-(R)-Pyrrolam A was synthesized via a key step reaction of a domino addition–Wittig alkenation reaction of (R)-benzyl prolinate with ylide the Ph₃PCCO, immobilized on a polystyrene resin (Scheme 1b).³ In addition, (+)-laburnine was synthesized via a strategy of photoinduced radical conjugate addition of a tertiary amine to the chiral furanone (Scheme 1c),⁴ and (−)-isoretronecanol was synthesized with the strategy of enamino ester reduction and the chiral induction originating from (S)-α-methylbenzylamine (Scheme 1d).⁵

Fig. 1 Select examples of naturally occurring pyrrolizidines and pyrrolizidine-3-ones.

Scheme 1 Select examples of the approaches to pyrrolizidines and pyrrolizidine-3-ones.

Apart from using natural chiral precursors, asymmetric total syntheses of pyrrolizidine derivatives employing enantioselective reactions as key step have been much less reported. For example, the proline-catalyzed sequential α-amination and the Horner–Wadsworth–Emmons olefination of aldehyde was developed (Scheme 1e),⁶ and the synthesis of trifluorinated heliotridan was realized by the enantioselective Friedel–Crafts reaction of β-trifluoromethylated acrylates with pyrroles (Scheme 1f).⁷

Despite the aforementioned success in the synthesis of indolizidine derivatives, an efficient and alternative approach to the asymmetric synthesis of this system remains compellingly attractive.⁸ Accordingly, in an effort to expand our study of the application of organocatalysis,⁹ we envisaged that the pot-economy sequential reactions¹⁰ could provide an efficient protocol for the enantioselective synthesis of the indolizidine derivatives (Scheme 2). Our synthetic strategy started from the retrosynthetic disconnection of tetrahydro-1H-pyrrolizin-3(2H)-one via amidation and reductive Mannich reaction, leading to methyl 4-amino-7-oxoheptanoate. Subsequent reduction transformation and Michael transformation of the aminoester would provide the chiral methyl 3-alkyl-4-nitrobutanoate and acrolein. The chiral nitroester could be obtained from the one-pot asymmetric Michael addition–oxidative esterification of α,β-unsaturated aldehydes. Herein, we reveal the details of this approach and the synthetic protocol that provided an enantioselective synthesis of chiral enriched indolizidines with only a one-step purification (two-pot operation) by sequential asymmetric Michael–oxidative esterification–Michael–reduction–reductive Mannich–amidation reactions.

Scheme 2 Retrosynthetic analysis of pyrrolizidine-3-one.

Initially, the γ-nitroesters 2 were prepared via a one-pot organocatalytic Michael addition–oxidative esterification of α,β-unsaturated aldehydes.¹¹ A series of enals 1 and nitromethane were reacted with a catalytic amount (10 mol%) of Jørgensen-Hayashi catalyst (I)¹² and benzoic acid (20 mol%) in MeOH at ambient temperature for 16 h (Table 1). Subsequently, the temperature of the solution was reduced to 4 °C and N-bromosuccinimide (NBS, 1.5–3.0 equiv.) was added to the reaction mixture, followed by stirring at 4 °C for 16 h. It is worth noting that the bromoproducts 2h and 2i were obtained in the reactions with the methoxy-substituted enals 1h and 1i. Via this one-pot protocol, the γ-nitroesters 2 were obtained in satisfactory yield, ranging from 53% to 66% with the enantioselectivity around 93–97% ee. The absolute stereochemistry of the γ-nitroesters was assigned unambiguously based on the X-ray analysis of a single crystal of (−)-2h (Fig. 2).

Table 1 Asymmetric Michael addition–oxidative esterification

Entry	R	Yield^a (%)	ee^b (%)
a Isolated yield.b Determined by HPLC with a chiral column (unless otherwise noted, by Chiralpak IB).c NBS (1.5 equiv.) was applied.d By Chiralpak IC.
1^c	2a: R1 = H, R2 = H, R3 = H, R4 = H	58	95
2^c	2b: R1 = H, R2 = F, R3 = H, R4 = H	62	94^d
3	2c: R1 = H, R2 = Cl, R3 = H, R4 = H	66	94
4	2d: R1 = H, R2 = Br, R3 = H, R4 = H	60	94
5	2e: R1 = H, R2 = Me, R3 = H, R4 = H	53	96
6	2f: R1 = Br, R2 = H, R3 = H, R4 = H	58	97
7	2g: R1 = Cl, R2 = H, R3 = Me, R4 = H	60	96
8	2h: R1 = H, R2 = OMe, R3 = H, R4 = Br	57	93
9	2i: R1 = OMe, R2 = H, R3 = F, R4 = Br	58	96

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Fig. 2 Stereoplots of the X-ray crystal structures of (−)-2h: C, gray; O, red; N, blue; Br, purple.

The conjugate addition of nitroester 2a to acrolein was screened with a series of catalysts and additives in CH₃CN (Table 2). Unusually, the reaction with triethyl amine (achiral base) provided the fastest completion and afforded the highest yield with highest diasteroselectivity (Table 2, entry 9).¹³ With the optimum reaction conditions in hand, a series of aminoesters 2 were reacted with acrolein and Et₃N to afford nitroaldehydes 3 (Table 3). All reactions were completed in a day and with the yields ranging from 78% to 89%. The enantiomeric excess value of the products 3 remained the same, around 93–97% ee. Notably, for the case with 2g bearing the ortho-methyl substituent, different diasteroselectiviy favoring anti-3 was observed, perhaps owing to the steric bulkiness so close to the conjugate addition center (Table 3, entry 7).

Table 2 Michael reaction of 2a and acrolein^a

Entry	Cat.	Additive	Solvent	Time (h)	Yield^d (%)	dr^e (syn-3a/anti-3a)
a Unless otherwise noted, the reactions were performed with catalyst-additive (20 mol%) in 0.1 M of 2a with a ratio of 1/2 of 2a and acrolein.b Recovered much starting materials (2a).c Additive (100 mol%).d Isolated yields.e Determined by the crude ^1H NMR spectrum. nr = no reaction. na = not available.
1^b	II	—	CH3CN	168	21	71 : 29
2^b	III	—	CH3CN	168	36	67 : 33
3	IV	—	CH3CN	168	nr	nr
4	V	—	CH3CN	144	52	47 : 53
5^b	I	PhCO2H	CH3CN	168	na	na
6	I	NEt3	CH3CN	50	32	72 : 28
7	II	NEt3	CH3CN	44	38	74 : 26
8	III	NEt3	CH3CN	24	61	68 : 32
9^c	—	NEt3	CH3CN	18	82	78 : 22
10^c	—	DIPEA	CH3CN	17	71	75 : 25
11	—	DBU	CH3CN	2	Trace	na
12	—	DABCO	CH3CN	18	47	69 : 31

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Table 3 Michael reaction of 2 and acrolein^a

Entry	R	Time (h)	Yield^b (%)	dr^c syn-3/anti-3	ee^d syn-3/anti-3
a The reactions were performed with NEt3 (1.0 equiv.) in 0.1 M of with a ratio of 1/2 of 2 and acrolein.b Isolated yields.c Determined by the crude ^1H NMR spectrum.d Determined by HPLC with a chiral column (Chiralpak IC).
1	3a: R1 = H, R2 = H, R3 = H, R4 = H	18	82	78 : 22	96/96
2	3b: R1 = H, R2 = F, R3 = H, R4 = H	24	86	71 : 29	95/96
3	3c: R1 = H, R2 = Cl, R3 = H, R4 = H	22	84	64 : 36	95/96
4	3d: R1 = H, R2 = Br, R3 = H, R4 = H	22	82	70 : 30	94/94
5	3e: R1 = H, R2 = Me, R3 = H, R4 = H	17	89	80 : 20	96/96
6	3f: R1 = Br, R2 = H, R3 = H, R4 = H	20	80	71 : 29	96/96
7	3g: R1 = Cl, R2 = H, R3 = Me, R4 = H	19	83	33 : 67	97/97
8	3h: R1 = H, R2 = OMe, R3 = H, R4 = Br	13	81	70 : 30	93/94
9	3i: R1 = OMe, R2 = H, R3 = F, R4 = Br	16	77	75 : 25	97/97

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Subsequently, the one-pot nitro reduction–reduction animation sequence of syn-3 was conducted with zinc powder (20 equiv.) in conc. aqueous HCl–MeOH (1 : 1 v/v, 0.1 mL) at 0 °C, followed by gradually warming to ambient temperature over 2 h. After the regular work up procedure (neutralization with aqueous NaHCO₃, extraction with EtOAc and concentration), the residue was dissolved in MeOH and the solution was heated to 50 °C for 12 h, affording the tetrahydro-1H-pyrrolizin-3 (2H)-one syn-4 in 51–77% yields (Table 4). The structure and, in particular, the absolute configuration of (−)-syn-4g was assigned unambiguously based on the X-ray analysis of a single crystal (Fig. 3). In particular, the asymmetric synthetic methodology to tetrahydro-1H-pyrrolizin-3(2H)-one could provide a useful protocol in the indolizidine natural products synthesis. For example, syn-4a has been transformed to phenopyrrozin, a marine metabolite isolated from the fungi Chromocleista sp.¹⁴

Table 4 Nitro reduction–reductive amination–lactamization of syn-3

Entry	R	Yield^a
a Isolated yield.
1	syn-4a: R1 = H, R2 = H, R3 = H, R4 = H	78
2	syn-4b: R1 = H, R2 = F, R3 = H, R4 = H	51
3	syn-4c: R1 = H, R2 = Cl, R3 = H, R4 = H	61
4	syn-4d: R1 = H, R2 = Br, R3 = H, R4 = H	55
5	syn-4e: R1 = H, R2 = Me, R3 = H, R4 = H	63
6	syn-4f: R1 = Br, R2 = H, R3 = H, R4 = H	68
7	syn-4g: R1 = Cl, R2 = H, R3 = Me, R4 = H	66
8	syn-4h: R1 = H, R2 = OMe, R3 = H, R4 = Br	57
9	syn-4i: R1 = OMe, R2 = H, R3 = F, R4 = Br	60

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Fig. 3 Stereoplots of the X-ray crystal structures of (−)-syn-4g: C, gray; O, red; N, blue; Cl, green.

On the other hand, the same reaction protocol was applied in the reaction of anti-3 and gave the corresponding tetrahydro-1H-pyrrolizin-3(2H)-one anti-4 in good yields, 52–76% yields (Table 5).

Table 5 Nitro reduction–reductive amination–lactamization of anti-3

Entry	R	Yield^a
a Isolated yield.
1	anti-4a: R1 = H, R2 = H, R3 = H, R4 = H	76
2	anti-4b: R1 = H, R2 = F, R3 = H, R4 = H	52
3	anti-4c: R1 = H, R2 = Cl, R3 = H, R4 = H	55
4	anti-4d: R1 = H, R2 = Br, R3 = H, R4 = H	59
5	anti-4e: R1 = H, R2 = Me, R3 = H, R4 = H	55
6	anti-4f: R1 = Br, R2 = H, R3 = H, R4 = H	53
7	anti-4g: R1 = Cl, R2 = H, R3 = Me, R4 = H	66
8	anti-4h: R1 = H, R2 = OMe, R3 = H, R4 = Br	64
9	anti-4i: R1 = OMe, R2 = H, R3 = F, R4 = Br	59

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Moreover, the four-step reaction, Michael–nitro reduction–reductive amination–lactamization, can be performed in a one-pot manner (Table 6). The isolated yields of 4 in this one-pot operation process were slightly higher than the corresponding stepwise operations from nitroester 2 and acrolein. The ee and dr of product 4 remained the same as that observed in the aforementioned aldehyde 3 isolation process.

Table 6 One-pot Michael–nitro reduction–reductive amination–lactamization

Entry	R	Time (h)	Yield^a (%)	dr^b syn-4/anti-4
a Isolated yield of pure syn-4/anti-4 mixture.b Determined by the crude ^1H NMR spectrum.c Further separation by HPLC with a ZORBAX SIL column gave 39% yield of syn-4a and 12% yield of anti-4a.d 94% and 94% ee, respectively. Determined by HPLC with a chiral column (Chiralpak IC).
1	4a: R1 = H, R2 = H, R3 = H, R4 = H	18	57^c	75 : 25
2	4d: R1 = H, R2 = Br, R3 = H, R4 = H	20	56	72 : 28^d
3	4h: R1 = H, R2 = OMe, R3 = H, R4 = Br	13	53	68 : 32

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Conclusions

In summary, we have reported an asymmetric synthesis of tetrahydro-1H-pyrrolizin-3(2H)-one from α,β-unsaturated aldehydes via a sequence of asymmetric Michael–oxidative esterification–Michael–reduction–reductive amination–lactamization with high enantioselectivities (93–97% ee). The six-step reaction sequence can be conducted with only a one-step purification, constituting the pot-economy synthetic strategy. The structures and absolute configurations of the products (−)-2h and (−)-syn-4g have been unambiguously confirmed by single crystal X-ray crystallographic analyses. Given the abundance of the indolizidine in nature, this efficient and asymmetric process could compose an effective protocol in a related natural product synthesis.¹⁴

Acknowledgements

We acknowledge the financial support for this study from the Ministry of Science and Technology (MOST, Taiwan) and thank the instrument center of MOST for analyses of compounds. Thanks to Arun Raja and Rui-You Xu for their help in the work.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental detail, spectroscopic characterization, HPLC analysis. CCDC 1420364 and 1420368. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra25103f

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